B-1 cells (formerly Ly-1 plus or CD5 plus B cells) are distinguished from conventional B (B-2) cells by numerous phenotypic, functional, and growth-related characteristics. B-1 cells are strongly associated with malignant transformation and autoimmune diseases. Despite much descriptive information about this subset/lineage, the molecular basis for B-1 cells constitutively express and activated STAT (Ptyr705STAT3) transcription factor (whereas B-2 cells do not) provides a new and potentially useful tool for understanding the development and behavior of the B-1 subset/lineage. The long-term objective of this work is to elucidate that underlying mechanisms responsible for B-1 cell features. The goals of the present application are to evaluation activated STAT3 as a sign of, and as a determinant of, B-1 development and function, and to test the hypothesis that activated STAT3 expression is responsible, at least in part, for the nature of B-1 cells. This will be accomplished through 4 specific aims. 1. Determine whether the subset/lineage-specific difference in Ptyr705STAT3 expression characterizes all stages of B-1 cell development, and the extent to which Ptyr705STAT3 is found in other B-1 related populations; 2. Identify the kinase responsible for phosphorylating STAT3 B-1 cells (constitutively) and B-2 cells (inducibly) and determine whether they are the same; 3. Assess the extent to which STAT3 expression directs B-1 cell development by analyzing transgenic mice that overexpress STAT3 and that express dominant negative STAT3; 4. Clone the murine cyclin D2 promoter that responds to PMA along in B-1 cells and determine the role of constitutive Ptyr705STAT3 expression in promoting cyclin D2 transcription. The information developed in this project will address key issues regarding the nature, development, and behavior of B-1 cells. This can reasonably be expected to lead to a better appreciation of targets that would be useful in regulating the growth and activities of B-1 cells that contribute to autoimmune and malignant dyscrasias.